A Good Side to Nicotine?

Nicotine holds promise for treating diseases such as attention deficit hyperactivity disorder (ADHD), Parkinson's and Alzheimer's diseases, and schizophrenia. "Nicotine is a very simple molecule, and it affects receptors of many subtypes; therefore, the consequences, behavioral and biologic, are very broad," says Neil Grunberg, director of the Psychoendocrinology and Biochemistry Laboratory at the Uniformed Services University of the Health Sciences. Nicotinic receptors control the release of numerous neurotransmitters, including dopamine, acetylcholine, and norepinephrine, "which are important in the acute minute-to-minute running of the brain, your emotions, cognitive aspects of memory," says G. Kenneth Lloyd, a scientific consultant in Poway, Calif. Nicotinic receptors are also involved in controlling nerve growth factors, important for the health of neurons. "The nicotinic receptors seem to be pretty important and pervasive," he comments. There are six different types of nicotinic receptors in humans, says Michael Williams, vice president of neurological and urological diseases at Abbott Pharmaceuticals, Abbott Park, Ill. Nicotine receptors are a subtype of receptors for the neurotransmitter acetylcholine. The receptors have five subunits surrounding an ion channel. Researchers at universities and at a number of major drug companies are working toward a better understanding of nicotine's effects, where in the body those effects are exerted, and how to develop compounds without nicotine's side effects. The work also entails mapping the location and structure of the numerous nicotine receptors on muscles and central and peripheral nerves, as well as conducting clinical trials of promising nicotine analogs or agonists. Williams says a total of nine pharmaceutical companies have nicotine research programs. Many disorders may respond to nicotine-based drugs. Imad Damaj, assistant professor of pharmacology at Virginia Commonwealth University, finds that nicotine or nicotine agonists may be nonopioid drugs to treat chronic pain. "We don't have a lot of agents for chronic pain. In animals we show that [nicotine] is active in chronic pain, inflammation, and neuropathic pain. Our data suggest there are some nicotinic receptors in the brain especially; they are involved in serotonin pathways, the brain stem, the thalamus, the cortex, and the spinal cord," he says. Chris Silber, head of the analgesia venture at Abbott, says that Abbott compound ABT 594 is already in Phase II clinical trials. Any successful nicotine agonist that is an analgesic would not have the side effects accompanying nicotine--increased heart rate and blood pressure and nausea, for example. Reprinted with permission:John Wiley & Sons, Muscle and Nerve JournalJon Lindstrom notes that nicotine agonists developed to target the a4b2 receptor (center) need to avoid a3 receptors, which can increase heart rate. Another area of interest is the structure of the analgesic receptor a4b2, notes Damaj. "The understanding of the receptor's structure will give us understanding of the pharmacology of the receptor and will give us new agonists and better, safer drugs," he comments. Nicotine is also being explored to help improve memory and attention. Problems with these mark diseases such as Alzheimer's and schizophrenia. Edward Levin, associate professor of psychiatry at Duke University, described at this year's annual meeting of the American Association for the Advancement of Science (AAAS) experiments in which nicotine given to normal subjects via the nicotine patch used in smoking cessation improved performance on an attention task. The task involved striking a key when a letter appeared on a computer screen and refraining from striking the key when a different letter appeared. "When we gave the nicotine skin patch, we saw a significant decline in errors of omission, and in the variability of their responding. [With the nicotine] they're more consistent in their responding. More importantly, we see this in patients with Alzheimer's disease," he says. Patients with "mild to moderate Alzheimer's disease" who wore the patch for four weeks also showed declines in errors of omission. This was a small study, Levin points out, involving only eight patients. Homing in on Hippocampus Levin is also examining the effects of nicotine on minimal cognitive impairment. This, he explains, is not full-blown Alzheimer's, but rather a "mild cognitive impairment" found in older people. "[Those with minimal cognitive impairment] run a much greater risk of developing Alzheimer's," he says. Nicotine may provide symptomatic relief, which he says he has seen, but more importantly, "there are some basic data to show there may be some longer-term effect attenuating the neurodegeneration." One potential site in the brain that nicotine may affect in this disorder is the hippocampus. " ... [The hippocampus has] long been known to be very important in terms of cognitive function, so the nicotinic receptors there seem to be very intimately involved in learning and memory," says Levin. Other areas such as the frontal cortex may also be involved. The hippocampus' nicotinic receptors might help increase understanding of schizophrenia and one of its widely observed characteristics: strong likelihood that those afflicted will smoke. The number of *7 nicotinic receptors in the hippocampi of schizophrenics is reduced compared to that of normal individuals. Though researchers such as Levin are not certain, they suspect that schizophrenics smoke in such high numbers--about 90 percent are smokers, compared to about 25 percent in the general population--as a way to medicate themselves and focus their attention. At the AAAS meeting, Levin noted that schizophrenics' performances improved on a variety of attention tasks when they were given the nicotine patch. He also noted that the patch reduced the sluggishness of their thought processes and the memory impairment that results from the antipsychotic medication haoperidol. Also, schizophrenics might smoke, Levin hypothesizes, to counteract the side effects of such medication. Grunberg hopes to get a better grasp of nicotine's role in schizophrenia by giving rats a drug that impairs attention and cognitive processing "in a way that mimics cognitive disruption in schizophrenia." He plans to see if nicotine mitigates that impairment by assessing the animal's ability to inhibit its response to a sudden loud noise. High smoking rates among another group of patients is one reason a nicotine-based drug developed by Abbott, ABT 418, is being examined in adult attention deficit hyperactive disorder. People with ADHD smoke earlier and in higher numbers than those without ADHD.1 Because the dopamine system in the brain is disrupted in ADHD and nicotine is involved in controlling this important neurotransmitter, "the idea [that] nicotine dysregulation could be involved in ADHD is a compelling one," says Joseph Biederman, professor of psychiatry at Harvard Medical School. In an exploratory double-blind, placebo-controlled study of this analog, Biederman and his colleagues found that ABT 418 both significantly reduced ADHD symptoms such as inability to pay attention to tasks and improved subjects' cognitive ability. "Drugs that enhance cognition may be very helpful for ADHD," says Biederman. But there's more to the ABT 418 story. Abbott initially explored its use in Alzheimer's. "The magnitude of the effect of that compound was not enough to justify continuing with that program," says Silber. The results "failed to show a differentiation from placebo," write Lloyd and Williams.2 The link between nicotinic receptors and dopamine is also being explored in Parkinson's disease, in which dopamine-releasing neurons are lost. Paul Newhouse, director of the clinical neuroscience research unit at the University of Vermont, discussed at the AAAS meeting preliminary experiments showing that nicotine, when given via the patch, reduced symptoms in Parkinson's patients. Problems to Solve Though there is a great deal of enthusiasm about exploiting nicotine to treat numerous maladies, there are, of course, hurdles to overcome. Jon Lindstrom, professor of neuroscience at the University of Pennsylvania, notes that specificity in targeting nicotine analogs is one important goal. He notes that nicotine agonists developed to target the *4ß2 receptor need to avoid another nicotine receptor, *3, which can increase heart rate. And both Lindstrom and Grunberg note that another challenge is in determining the precise link between given receptors and their function. But a success, says Lindstrom, can pay many dividends: "Success with one of these drugs will float everybody's boat. It will help the drug company that comes up with it and will enhance the perceived significance of the basic research into these." Whether that will happen, of course, remains a major question. Robert Mansbach, a senior investigator at Pfizer Inc., N.Y., points out, "There's always a lot of enthusiasm before the clinical data come in. A lot of this stuff may very well not pan out. A lot of [it is] based on animal data and speculation. There are examples in the past of the promise not completely panning out." Harvey Black is a freelance science writer in Madison, Wis. References 1. T.E. Wilens et al., "A pilot controlled trial of ABT-418, a cholinergic agonist in the treatment of adults with attention deficit hyperactivity disorder," American Journal of Psychiatry, 156:1931-7, 1999. 2. G.K. Lloyd, M. Williams, "Neuronal nicotinic acetylcholine receptors as novel drug targets," Journal of Pharmacology and Experimental Therapeutics, 292:461-7, February 2000.

A Good Side to Nicotine?

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